Fibrosis is a general term used to describe excessive formation and/or development of fibrous connective tissues in mammalian tissues and organs as a consequence of an injury reparative process or a reaction to an abnormal causative agent. Prolonged fibrosis typically results in localized scarring of tissues and/or organs to the point where their physiological functions are impaired. Mammalian tissues and organs commonly affected by fibrosis include skin (e.g., sclerodermic fibrosis; keloid fibrosis), the heart (cardiac fibrosis; endomyocardial fibrosis), lungs (pulmonary fibrosis), liver (cirrhosis), and kidneys (nephrogenic fibrosis) among others. Fibrosis is associated with the over-production of collagen proteins which are the primary protein constituents of connective tissues.
Recent published information indicates that development of cardiac fibrosis resulting from tissue damage that occurs during myocardial infarctions is a consequence of a significant increase in scleraxis proteins in the damaged cardiac tissue areas. The increased scleraxis levels appear to be directly related to the activation of cardiac fibroblasts that are subsequently phenoconverted to myofibroblasts as part of the wound healing response. Concomitant changes occurring in the damaged cardiac tissue include degradation of necrotic myocytes, repopulation of the damaged infarct area by myofibroblasts, and subsequent remodeling of the surrounding extracellular matrix (ECM) to form scar tissues. Although the mechanisms controlling the phenoconversion of cardiac fibroblasts to myofibroblasts are not yet well understood, it appears that this differentiation process is strongly promoted by the fibrotic agent TGF-β1 which in turn, appears to cause increased scleraxis protein levels in the damaged areas. Collagen production is regulated in part by the COL1α2 gene. The proximal COL1α2 gene promoter is responsive to TGF-β1 signaling and to scleraxis. Accordingly, increasing levels of scleraxis proteins directly or in response to TGF-β1 signaling in infarct-affected tissues will promote COL1α2 gene expression and production of collagen.
The activation of the cardiac fibroblasts and their phenoconversion to myofibroblasts significantly increases expression and proliferation of types I, III and V fibrillar collagens in the infarct-damaged areas. However, post-infarct development and proliferation of cardiac scar tissue often extends beyond damaged areas to the point where the cardiac contractility is impaired, and thereby may contribute to heart failure. There is need, therefore, for compositions and therapies that will enable selective inhibition of the expression of COL1α2 genes in damaged tissues.